JP2843634B2 - Xanthine derivative - Google Patents

Abstract

Novel xanthine compounds represented by the following formula: <CHEM> and pharmaceutically acceptable salts thereof have a diuretic action, a renal-protecting action and a vasodilative action. The compounds are useful as a diuretic, a renal-protecting agent and an antihypertensive agent.

Description

Description: TECHNICAL FIELD The present invention relates to a novel xanthine derivative having a diuretic effect, a renal protective effect and a vasodilatory effect.

2. Description of the Related Art Conventionally, theophylline (1,3-dimethylxanthine) is known as a diuretic, a vasodilator and the like [The Merck Index, 10th edition, p. 9110 (1983)].

Further, in the theophylline analogs represented by the following general formula (I), R ⁴ and R ⁵ both have an alkyl group and exhibit a diuretic effect, which is described in East German Patent 31,772 [Chem. Abst., 63 ,
18120d (1965)]; West German Patent 1,245,969 [Chem. Abst., 6
7 , 90994n (1967)]; J. Am. Chem. Soc., 75 , 114 (1953) and J. Med. Chem., 14 , 1202 (1971) show a bronchodilator effect. JP-A-56-166191; 57-163381
Japanese Patent Application Laid-Open No. 55-6658 discloses a xanthine derivative having other activities such as anti-inflammatory activity.
No. 3, JP-A-61-500666; U.S. Pat. No. 3,624,2
No. 15, No. 3,624,216 and the like.

An object of the present invention is to provide a novel xanthine derivative having a diuretic effect, a renal protective effect, a vasodilatory effect, and the aforementioned R ⁴ and R ⁵ are alicyclic alkyl or aryl. It is in.

Means for Solving the Problems The present invention provides a compound of the formula (I) (Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl, and R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alicyclic alkyl or substituted or unsubstituted Wherein X ¹ or X ² is the same or different and represents an oxygen or sulfur atom) [hereinafter referred to as compound (I)]. The same applies to compounds of other formula numbers] or a pharmacologically acceptable salt thereof.

In the definition of each group of formula (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Butyl, n-pentyl, neopentyl, n-hexyl and the like, and alicyclic alkyls having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like can be mentioned. Aryl includes phenyl, naphthyl and the like. Here, the substituents of the alicyclic alkyl and aryl may be the same or different and have 1 to 3 substituents.
For example, lower alkyl, hydroxy, lower alkoxy, halogen, amino, nitro and the like can be mentioned, and the alkyl portion of lower alkyl and lower alkoxy is the same as the definition of lower alkyl, and halogen is fluorine, chlorine, bromine, iodine. Is included.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.

The pharmacologically acceptable acid addition salts of compound (I) include
Inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, etc., and as pharmacologically acceptable metal salts, In addition to alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt, calcium salt and the like, aluminum salts and zinc salts are also mentioned, and ammonium salts include salts such as ammonium and tetramethylammonium. The pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and the pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine and phenylalanine.

 Hereinafter, the method for producing the compound of the present invention will be described.

Compound (Ia) wherein R ³ is hydrogen in compound (I)
Can be obtained according to the following manufacturing steps.

(Wherein, Hal represents a halogen atom of chlorine, bromine or iodine, and R ¹ , R ² , R ⁴ , R ⁵ , X ¹ and X ² have the same meanings as described above) Step 1: A known method (for example, Uracil derivative (II) and carboxylic acid (II) obtained according to JP-A-59-42383).
Compound (IV) can be obtained by reacting with I) or a reactive derivative thereof.

Examples of the reactive derivative of the carboxylic acid include acid halides such as acid chloride and acid bromide, active esters such as p-nitrophenyl ester and N-oxysuccinimide ester, and commercially available or 1-ethyl-3- (3 (Dimethylaminopropyl) carbodiimide, diisopropyl carbodiimide, dicyclohexyl carbodiimide and the like, and acid anhydrides produced using carbodiimides, mixed acid anhydrides with monoethyl carbonate, monoisobutyl carbonate and the like.

The reaction can be carried out using compound (III) and heating to 50 to 200 ° C. without a solvent, but when reacting as a reactive derivative, the reaction should be carried out according to a method commonly used in peptide chemistry. Can be. For example, as the reaction solvent, methylene chloride, chloroform, halogenated hydrocarbons such as ethane dichloride, dioxane, ethers such as tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and water and the like are appropriately selected,
The reaction is carried out at a temperature of -80 to 50 ° C, and the reaction is completed in 0.5 to 24 hours. If necessary, the reaction can be advantageously carried out in the presence of an additive such as 1-hydroxybenzotriazole or a base such as pyridine, triethylamine, dimethylaminopyridine or N-methylmorpholine. The reactive derivative may be used in the reaction system without isolation.

Step 2: Compound (IV) is subjected to treatment with a dehydrating agent (Method B) or heating (Method C) in the presence of a base (Method A) to give the target compound (Ia).

Examples of the base suitably used in the method A include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The reaction solvent is water, lower alcohols such as methanol and ethanol, dioxane, ethers such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like are used alone or in combination, and the reaction is carried out at room temperature to 180 ° C., usually for 10 minutes to Finish in 6 hours.

As the dehydrating agent in the method B, for example, thionyl halides such as thionyl chloride, phosphorus oxyhalides such as phosphorus oxychloride are used, and no solvents or halogenated hydrocarbons such as methylene chloride, chloroform and ethane dichloride; Performed at room temperature to 180 ° C. in a solvent inert to a reaction such as dimethylformamide and dimethyl sulfoxide,
Usually ends in 0.5 to 12 hours.

In the method C, the compound (Ia) can be obtained by heating to 50 to 200 ° C. in a polar solvent such as dimethyl sulfoxide, dimethylformamide, Dowthermo A (Muromachi Chemical Industry Co., Ltd.).

Step 3: Compound (II) and aldehyde (V) are reacted at a temperature of −20 to 100 ° C. in a mixed solvent of acetic acid and a lower alcohol such as methanol or ethanol to obtain Schiff base (VI). it can.

Step 4: The target compound (Ia) can be obtained by subjecting the compound (VI) to an oxidative cyclization reaction.

Suitable oxidizing agents include, for example, oxygen, ferric chloride, cerium (IV) ammonium nitrate, diethyl azodicarboxylate and the like. The reaction is carried out, if necessary, in the presence of the above oxidizing agent, such as reaction of lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, or aromatic hydrocarbons such as toluene, xylene and nitrobenzene. In an inert solvent,
It is performed by heating from room temperature to 180 ° C.

Step 5: A uracil derivative (VII) and an amine (VIII) obtained according to a known method (for example, JP-A-61-5082) are converted to lower alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide and the like. In a solvent inert to the reaction alone or in a mixed solvent, usually 50 to 150 ° C
The compound (IX) can be obtained by heating to.

Step 6: Compound (IX) and a nitrous acid derivative such as sodium nitrite and isoamyl nitrite as a nitrosating agent in an inert solvent such as lower alcohols such as methanol and ethanol under acidic conditions such as dilute hydrochloric acid. Usually, compound (Ia) can be obtained by heating from room temperature to the boiling point of the solvent.

Step 7: Compound (Ib) in which R ³ is lower alkyl in compound (I) can be obtained according to the following production steps.

(Wherein, R ¹ , R ² , R ⁴ , R ⁵ , X ¹ and X ² are as defined above,
R ^3a represents lower alkyl in the definition of R ³ , and L represents a leaving group. Here, the leaving group includes a halogen atom such as bromine and iodine, an alkylsulfonyloxy group such as methanesulfonyloxy, and p-toluene. An arylsulfonyloxy group such as sulfonyloxy is exemplified.

The target compound (Ib) can be obtained by reacting the compound (Ia) obtained by the above-mentioned production method with the alkylating agent (X), preferably in the presence of chloride. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. And usually ends in 0.5 to 24 hours.

Step 8: Compound (Id) wherein X ² in compound (I) is sulfur
Can be obtained according to the following manufacturing process.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and X ¹ have the same meanings as described above). (Ic) obtained by the above-mentioned production method [In the compound (I), X ² is Compound which is oxygen] with an appropriate thiolating agent to give the desired compound (Id). Examples of the thiolating agent include phosphorus pentasulfide and the like, and examples of the solvent include dimethylformamide, tetrahydrofuran, dioxane and the like, and more preferably pyridine and the like. The reaction is completed at 50 to 180 ° C for 10 minutes to 12 hours.

Intermediates and target compounds in the above-mentioned production method,
Purification methods commonly used in synthetic organic chemistry, such as extraction, extraction,
It can be isolated and purified by washing, drying, concentration, recrystallization, various chromatographies and the like. In addition, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is,
When it is obtained in a free form, a salt may be formed by an ordinary method.

The compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Although some of the compounds (I) may have optical isomers, the present invention also includes all possible stereoisomers and mixtures thereof.

Table 1 shows specific examples of the compound (I). The compound numbers in the table correspond to the example numbers described later.

The compound (I) of the present invention and a pharmacologically acceptable salt have a diuretic effect, a renal protective effect and a vasodilatory effect. Therefore, compound (I) is useful as a diuretic, a renal protective agent and an antihypertensive.

Next, the pharmacological action of the compound (I) will be described in Test Examples.

Test Example 1. Diuretic action Wistar rats (male; 150 to 300 g) were used after being starved for 18 hours after feeding was cut off. The test compound was orally administered (dose; 25 mg / kg) to the test rat, and urine was collected for 6 hours. The experiment was performed on three rats per test compound, with three rats per group. Urine is measured with a measuring cylinder, and the urine electrolytes (Na ⁺ and K ⁺ ) are measured with a flame photometer (Hitachi 7
75A).

 The results are shown in Table 2.

In addition, all the parameters in the table were compared and expressed using a pharmacologically untreated rat as a control.

As can be seen in Table 2, compounds 1, 4 and 11 showed greater activity than the reference compound in urine volume and Na ⁺ to K ⁺ ratio.

Test Example 2. Renal Protective Effect (Glycerol-Induced Renal Failure Model) Renal failure is a state in which renal function is reduced and body fluid homeostasis cannot be maintained. It is known that subcutaneous or intramuscular injection of glycerol in rats induces acute renal failure characterized by tubular injury [Can. J. Physiol.
macol., 65 , 42 (1987)].

Wistar rats (male) were used 18 hours after water intake was cut off. Intraperitoneal administration of test compound (dose; 0.1 ml
30 minutes later, the rats were anesthetized with ether, the skin on the back was pinched, and 0.8 ml / 100 g of 50% glycerol was subcutaneously administered. Twenty-four hours after glycerol administration, the rats were anesthetized with ether, and 5 ml of blood was collected from the descending aorta. 3 samples collected
After standing for 0 minutes or more, the mixture was centrifuged at 3000 rpm for 10 minutes, and creatinine in the obtained serum was subjected to creatinine-Test Wako (Jaf).
f'e method).

On the other hand, the kidney on the left side of the collected blood was removed and placed in a vial containing formalin. A kidney-untreated rat kidney similarly removed was used as a control and used as a sample for pathological findings.

According to the test results, Compounds 1, 8 and 11 showed 10 mg / k
g Intraperitoneal administration significantly suppressed the increase in serum creatinine level (Compound 1: p <0.05; Compound 8: p <0.001; Compound 11: p <0.001), while aminophylline almost inhibited the increase. Not shown, furosemide showed a tendency to worsen. Compounds 1 and 8 also showed a significant improvement in the pathological findings of the isolated kidney.

Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms.
The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient. Desirably, these pharmaceutical compositions are in unit dosage form suitable for administration orally or by injection.

In preparing the compositions in oral dosage form, any useful pharmaceutically acceptable carrier can be used. Oral liquid preparations, such as, for example, suspensions and syrups,
Water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil, soybean oil, preservatives such as p-hydroxybenzoic acid esters, strawberry flavor, peppermint, etc. It can be manufactured by using flavors and the like. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, polyvinyl alcohol, hydroxypropyl It can be produced using a binder such as cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When producing tablets and capsules, an individual pharmaceutical carrier is used.

Further, the solution for injection can be prepared using a carrier composed of distilled water, a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution.

The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, the age, weight, and symptoms of the patient, but are usually 1 to 50 mg / k per day.
g is preferably administered in three to four divided doses.

 Hereinafter, examples of the present invention will be described.

Example 1. 8- (1,1-Dicyclopropylmethyl) -1,3-dipropylxanthine (Compound 1) 1.40 g (10 mmol) of 1,1-dicyclopropylacetic acid was dissolved in 25 ml of pyridine, After addition of 0.78 ml (11 mmol) of thionyl, the mixture was stirred at 60 ° C. for 10 minutes. Then, under ice cooling, 2.26 g of 5,6-diamino-1,3-dipropyluracil (1
(0 mmol) in 15 ml of pyridine and stirred for 1 hour. After concentrating the solvent under reduced pressure about half, it was poured into ice water and extracted three times with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluting solvent: 10% methanol / chloroform) to give amorphous 6-amino-5- (1,1-dicyclopropyl) acetylamino-1,3-dipropyluracil [ Compound (IV): 2.33 g (67% yield) was obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.71 (brs, 1H), 5.52 (b
rs, 2H), 4.00-3.75 (m, 4H), 1.90-1.50 (m, 4H), 1.40
0.20.20 (m, 17H) To the above compound was added 10 ml of phosphorus oxychloride, and the mixture was heated under reflux for 2 hours. After concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted to 6.5 with a 2N aqueous sodium hydroxide solution. This was extracted three times with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent; 30%
After separation and purification with ethyl acetate / hexane, recrystallization from ethanol-water gave 1.33 g (60%) of the title compound 1 as white needles.
%).

Mp: from 129.1 to 130.4 ° C. Elemental analysis _{(C 18 H 26 N 4 O} 2) theory (%): C65.43, H7.93, N16.96 Found (%): C65.53, H8.11, N16 .82 IR (KBr) νmax (cm ^-1 ): 1700,1654,1498 NMR (CDCl ₃ ; 270 MHz) δ (ppm): 12.70 (brs, 1H), 4.13
(T, 2H), 3.97 (t, 2H), 1.90 ~ 1.60 (m, 5H), 1.50 ~ 1.3
5 (m, 2H), 1.10 to 0.90 (m, 6H), 0.75 to 0.60 (m, 2H), 0.
Example 2. 8- (1,1-diphenylmethyl) -1,3-dipropylxanthine (compound 2) 5,6-diamino-1,3-dipropyluracil 2.00 g (50-0.20 (m, 6H)) 8.8
5 mmol) was dissolved in 10 ml of pyridine, and 2.45 g (10.6 mmol) of diphenylacetyl chloride was added under ice cooling. Four
After stirring for 0 minutes, the mixture was poured into ice water and extracted three times with toluene. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 6-amino-5- (1,1-diphenyl) in irregular shape.
Acetylamino-1,3-dipropyluracil [compound (I
V): 3.92 g (quantitative) were obtained.

To 3.62 g of the above compound, 36 ml of dioxane and 36 ml of a 2N aqueous sodium hydroxide solution were added, and the mixture was heated under reflux for 35 minutes.
After cooling, the mixture was neutralized, extracted three times with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent; 30% ethyl acetate / hexane), and recrystallized from cyclohexane to give 2.53 g (total yield: 86%) of the title compound 2 as a white powder.

Mp: from 167.1 to 168.5 ° C. Elemental analysis _{(C 24 H 26 N 4 O} 2) theory (%): C71.62, H6.51, N13.92 Found (%): C71.65, H6.51, N13 .70 IR (KBr) νmax (cm -1): 1708,1649,1557,1493 NMR (CDCl 3; 90MHz) δ (ppm): 7.35~7.05 (m, 10H), 5.
68 (s, 1H), 4.20 to 3.75 (m, 4H), 1.95 to 1.45 (m, 4H),
1.10 to 0.80 (m, 6H) Example 3.8 8- (1-cyclopentyl-1-phenylmethyl) -1,
3-dipropylxanthine (compound 3) 2.00 g of 5,6-diamino-1,3-dipropyluracil (8.8 g
5 mmol) in a solution of 40 ml of dioxane and 20 ml of water,
2.17 g (10.62 mmol) of 2-phenylcyclopentaneacetic acid and 2.04 g (10.62 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 4 hours while adjusting to pH 5.5. did. pH
The mixture was extracted with chloroform three times, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (extraction solvent: 2% methanol / chloroform) to give 6-amino-5- (1-cyclopentyl-1-phenyl) acetylamino-1,3-dipropyluracil in irregular shape. [Compound (IV): 1.73 g (47%) were obtained.

MS (m / e): 412,253,226,225,159,91 NMR (CDCl 3; 90MHz) δ (ppm): 7.50~7.00 (m, 5H), 5.2
2 (brs, 2H), 4.00 to 3.60 (m, 4H), 3.28 (d, 1H, J = 11H
z), 2.8 to 2.45 (m, 1H), 2.10 to 0.80 (m, 18H) Phosphorus oxychloride was added to 1.28 g (3.11 mmol) of the above compound.
3 ml was added, and the mixture was heated under reflux for 30 minutes. This was concentrated under reduced pressure, the residue was poured into ice water, and adjusted to pH 6.5 with a 2N aqueous sodium hydroxide solution. After extracting three times with chloroform,
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: 25% ethyl acetate / hexane), and recrystallized from isopropanol-water to obtain 730 mg (59%) of the title compound 3, as a white powder.

Mp: from 136.6 to 138.1 ° C. Elemental analysis _{(C 23 H 30 N 4 O} 2) theory (%): C70.02, H7.66, N14.20 Found (%): C69.91, H7.77, N14 .14 IR (KBr) νmax (cm ^-1 ): 1703,1654,1496 NMR (CDCl ₃ ; 270 MHz) δ (ppm): 12.80 (brs, 1H), 7.60
~ 7.15 (m, 5H), 4.20 ~ 4.05 (m, 4H), 3.90 (d, 1H, J = 1
1.0Hz), 3.10-2.90 (m, 1H), 2.00-1.50 (m, 10H), 1.3
0-0.90 (m, 8H) Example 4. 8- (1-Cyclopropyl-1-phenylmethyl) -1,
3-Dipropylxanthine (compound 4) 1-cyclopropyl-1-phenylacetic acid [Pestic.Sc
i., 11 , 513 (1980)] in a solution of 1.55 g (8.76 mmol) and 5,6-diamino-1,3-dipropyluracil (1,80 g, 7.96 mmol) in 36 ml of dioxane and 18 ml of water at room temperature,
1.84 g (9.56 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was adjusted to pH 5.5.
And stirred for 2 hours. After adjusting the pH to 7.5, the mixture was extracted three times with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: 1.5%
Separation and purification with methanol / chloroform) to give 6-amino-5- (1-cyclopropyl-1-phenyl) acetylamino-1,3-dipropyluracil (compound (IV): 2.07 g (61%) were obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.70 (brs, 1H), 7.40-
7.15 (m, 5H), 5.42 (brs, 2H), 4.00 to 3.65 (m, 4H), 2.9
3 (d, 1H, J = 10 Hz), 1.95 to 1.25 (m, 5H), 1.10 to 0.20
(M, 10H) 1.90 g (4.95 mmol) of the above compound and 30 m of dioxane
l, 1N aqueous sodium hydroxide solution (40 ml) was added, and the mixture was heated under reflux for 15 minutes. After neutralization, the mixture was concentrated to about 2/3, extracted three times with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent; 30% ethyl acetate / hexane) and recrystallized from cyclohexane to give 1.77 g (93%) of the title compound 4 as a white powder.

Mp: from 153.9 to 155.1 ° C. Elemental analysis _{(C 21 H 26 N 4 O} 2) theory (%): C68.83, H7.15, N15.29 Found (%): C69.06, H7.42, N15 .34 IR (KBr) νmax (cm ^-1 ): 1709,1652,1497 NMR (CDCl ₃ ; 270 MHz) δ (ppm): 13.11 (brs, 1H), 7.50
~ 7.40 (m, 2H), 7.35 ~ 7.15 (m, 3H), 4.12 (t, 2H), 3.9
8 (t, 2H), 3.46 (d, 1H, J = 10.3Hz), 1.95 to 1.65 (m, 5
H), 1.05-0.90 (m, 6H), 0.80-0.65 (m, 2H), 0.50-0.
35 (m, 2H) Example 5.8 8- [1-Cyclopropyl-1- (4-methoxyphenyl) methyl] -1,3-dipropylxanthine (compound 5) 1-cyclopropyl-1- (4- Methoxyphenyl)
Acetic acid [Pestic. Sci., 11 , 513 (1980)] 1.57 g (7.61 mmol) and 5,6-diamino-1,3-dipropyluracil 1.56
Using g (6.92 mmol), substantially the same operation as in Example 4 was carried out to give amorphous 6-amino-5- [1-cyclopropyl-1- (4-methoxyphenyl)] acetylamino-1,3- Dipropyluracil [compound (IV): 1.72 g (53%) were obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.67 (brs, 1H), 7.28
(D, 2H, J = 9Hz), 6.83 (d, 2H, J = 9Hz), 5.43 (brs, 2
H), 4.00 to 3.70 (m, 4H), 3.79 (s, 3H), 2.92 (d, 1H, J =
10 Hz), 1.95 to 1.25 (m, 5H), 1.10 to 0.20 (m, 10H) Example 4 using 1.60 g (3.86 mmol) of the above compound
By substantially the same operation as described above, recrystallization from isopropanol-water gave 1.23 g (76%) of the title compound 5 as white needles.

Mp: from 142.5 to 143.7 ° C. Elemental analysis _{(C 22 H 28 N 4 O} 3) theory (%): C66.64, H7.12, N14.13 Found (%): C66.70, H7.35, N14 .24 IR (KBr) νmax (cm ^-1 ): 1710,1651,1514,1498 NMR (CDCl ₃ ; 270 MHz) δ (ppm): 12.46 (brs, 1H), 7.38
(D, 2H, J = 9.6Hz), 6.85 (d, 2H, J = 9.6Hz), 4.11 (t, 2
H), 3.98 (t, 2H), 3.78 (s, 3H), 3.42 (d, 1H, J = 10.0H
z), 1.90-1.60 (m, 5H), 1.10-0.95 (m, 6H), 0.80-0.
Example 6.8 8- [1-Cyclopropyl-1- (4-fluorophenyl) methyl] -1,3-dipropylxanthine (Compound 6) 1 60 (m, 2H), 0.50 to 0.30 (m, 2H) -Cyclopropyl-1- (4-fluorophenyl)
Acetic acid [Pestic. Sci., 11 , 513 (1980)] 1.89 g (9.73 mmol) and 5,6-diamino-1,3-dipropyluracil 2.00
Using g (8.85 mmol), substantially the same operation as in Example 4 was carried out to give an indefinite form of 6-amino-5- [1-cyclopropyl-1- (4-fluorophenyl)] acetylamino-1,3- Dipropyluracil [compound (IV): 1.91 g (49%) were obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.73 (brs, 1H), 7.33 (d
d, 2H, J = 5.9 Hz), 7.01 (dd, 2H, J = 9.9 Hz), 5.42 (brs, 2
H), 4.00-3.70 (m, 4H), 2.91 (d, 1H, J = 10 Hz), 2.00-
1.25 (m, 5H), 1.10 to 0.20 (m, 10H) Example 4 using 1.75 g (4.35 mmol) of the above compound
By substantially the same operation as described above, recrystallization from isopropanol-water gave 1.41 g (80%) of the title compound 6 as white needles.

Mp: from 156.2 to 157.8 ° C. Elemental analysis _{(C 21 H 25 FN 4 O} 2) theory (%): C65.61, H6.55, N14.57 Found (%): C65.57, H6.70, N14 .69 IR (KBr) νmax (cm ^-1 ): 1710,1653,1510,1498 NMR (CDCl ₃ ; 270 MHz) δ (ppm): 12.62 (brs, 1H), 7.45
(Dd, 2H, J = 5.3,8.5Hz), 7.01 (dd, 2H, J = 8.5 8.5Hz),
4.12 (t, 2H), 3.98 (t, 2H), 1.90 to 1.65 (m, 5H), 1.10
~ 0.95 (m, 6H), 0.80 ~ 0.60 (m, 4H), 0.50 ~ 0.35 (m, 2
H) Example 7.8 8- (1,1-Dicyclohexylmethyl) -1,3-dipropylxanthine (Compound 7) 2.19 g (9.74 mmol) of 1,1-dicyclohexylacetic acid was dissolved in 30 ml of pyridine, and 0.78 of thionyl chloride was dissolved. ml (11 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then under ice cooling,
2.00 g of 5,6-diamino-1,3-dipropyluracil (8.85
(Mmol) in 10 ml of pyridine and stirred for 1 hour. After adding 50 ml of toluene, the mixture was concentrated to about 1/3, poured into ice water, and extracted three times with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent; 1% methanol / chloroform) to give an indefinite form of 6-amino-5-
(1,1-dicyclohexyl) acetylamino-1,3-dipropyluracil [compound (IV); 3.79 g (99%) were obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.19 (brs, 1H), 5.52 (b
rs, 2H), 4.00-3.70 (m, 4H), 2.10-0.75 (m, 33H) 3.50 g (8.10 mmol) of the above compound was treated with phosphorus oxychloride 3
5 ml was added, and the mixture was heated under reflux for 2 hours. After concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted with 2N aqueous sodium hydroxide solution.
Was adjusted to 6.5. This is extracted three times with chloroform,
After washing with saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent; 15% ethyl acetate / hexane), and recrystallized from cyclohexane to give 2.58 g (77%) of the title compound 7 as a white powder.

Melting point: 198.3-200.1 ° C MS (m / e): 414 (M ⁺ ), 332,331,289 IR (KBr) νmax (cm ^-1 ): 1700, 1650, 1498 NMR (DMSO-d ₆ ; 270 MHz) δ (ppm): 12.96 (brs, 1H), 3.
97 (t, 2H), 3.83 (t, 2H), 2.45 (t, 1H, J = 7.8Hz), 1.90
~ 8.8 (m, 32H) Example 8.8- [1,1-Di (2-methylcyclopropyl) methyl]
-1,3-Dipropylxanthine (diastereomeric mixture) (compound 8) 1,1-di (2-methylcyclopropyl) acetic acid 980 mg (5.
83 mmol) and 1.20 g (5.30 mmol) of 5,6-diamino-1,3-dipropyluracil were obtained in substantially the same manner as in Example 7 to give an indefinite form of 6-amino-5- [1,1- Di (2-methylcyclopropyl)] acetylamino-1,3
-Dipropyluracil [compound (IV): 1.20 g (60%) were obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.58 (brs, 1H), 5.52 (b
rs, 2H), 4.00 to 3.75 (m, 4H), 2.00 to 0.20 (m, 25H) Example 7 was conducted using 1.20 g (3.18 mmol) of the above compound.
The title compound 8, 885 m
g (78%) was obtained.

Melting point: 67.2-70.3 ° C MS (m / e): 358 (M ⁺ ), 303,287 IR (KBr) νmax (cm ^-1 ): 1700, 1655 (shoulder), 1650, 1498 NMR (CDCl ₃ ; 270 MHz) δ ( ppm): 12.65 to 12.30 (brm, 1
H), 4.11 (t, 2H), 3.99 (t, 2H), 2.20 to 0.20 (m, 25H) HPLC [AM-312 (YMC150 × 5φ), 50% acetonitrile
Water, UV271nm, 2.0ml / min]: Retention time (relative area); 16.9 minutes (19), 17.8 minutes (30), 19.
7 minutes (21), 20.5 minutes (30) Example 9. 8- (1,1-Dicyclopropylmethyl) -1,3-dipropyl-2-thioxanthine (compound 9) 1,1-dicyclopropylacetic acid 1.27 g (9.09 mmol)
Using 2.00 g (8.26 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil [J. Med. Chem., 32 , 1873 (1989)], the same operation as in Example 1 was performed. 6-amino-5- (1,1-dicyclopropyl) acetylamino-1,3-dipropyl-2-thiouracil of irregular shape [compound (IV): 2.42 g (81% yield) was obtained.

NMR (CDCl ₃ ; 90 MHz) δ (ppm): 7.75 (brs, 1H), 5.70 (b
rs, 2H), 4.60-4.20 (m, 4H), 2.05-0.20 (m, 21H) Example 1 was carried out using 2.00 g (5.49 mmol) of the above compound.
Approximately the same operation as above was carried out, and recrystallized from ethanol-water to obtain 1.09 g (57%) of the title compound 9 as white needles.

Mp: from 153.8 to 156.4 ° C. Elemental analysis _{(C 18 H 26 N 4 OS} ) theory (%) C62.40, H7.56, N16.17 Found (%) C62.71, H7.94, N16.24 IR (KBr) νmax (cm ^-1 ): 1674,1493,1408 NMR (CDCl ₃ ; 270 MHz) δ (ppm); 12.79 (brs, 1H), 4.69
(T, 2H), 4.57 (t, 2H), 2.00 ~ 1.70 (m, 5H), 1.50 ~ 1.3
5 (m, 2H), 1.10 to 0.95 (m, 6H), 0.80 to 0.60 (m, 2H), 0.
50-0.20 (m, 6H) Example 10. 8- (1,1-Dicyclopropylmethyl) -3-propylxanthine (Compound 10) 1.68 g (12.0 mmol) of 1,1-dicyclopropylacetic acid
Using 2.00 g (10.9 mmol) of 5,6-diamino-3-propyluracil, the same operation as in Example 1 was carried out.
-Amino-5- (1,1-dicyclopropyl) acetylamino-3-propyluracil [compound (IV): 1.07 g (51%) was obtained as a pale yellow powder.

NMR (DMSO-d ₆ ; 90 MHz) δ (ppm): 10.55 (brs, 1H), 8.1
6 (brs, 1H), 6.05 (brs, 2H), 3.73 (t, 2H), 1.80-0.10
(M, 16H) To 2.00 g (6.54 mmol) of the above compound was added 40 ml of a 2N aqueous sodium hydroxide solution and 20 ml of dioxane, and the mixture was heated under reflux for 2 hours. After cooling, the mixture was neutralized, extracted three times with chloroform-methanol (9: 1), washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (elution solvent: 2% methanol / chloroform), and then recrystallized from ethanol to give the title compound (10, 859m) as a white plate.
g (45%) was obtained.

Mp: 271.8~277.8 ℃ IR (KBr) νmax (cm -1): 1694,1660,1499 NMR (DMSO-d 6, 90MHz) δ (ppm): 13.03 (brs, 1H), 10.
92 (brs, 1H), 3.85 (t, 2H), 1.90-0.05 (m, 16H) MS (m / e): 288 (M ⁺ ) Example 1 1. 8- (1,1-dicyclopropylmethyl) -1,3-Dipropyl-7-methylxanthine (compound 11) In a solution of 2.00 g (6.05 mmol) of compound 1 obtained in Example 1 in 60 ml of dimethylformamide, 2.09 g (15.1 mmol) of potassium carbonate and 0.75 methyl iodide were added. ml (1
2.1 mmol) and stirred at 50 ° C. for 1 hour. After cooling, insolubles were separated and concentrated under reduced pressure. 200 ml of water was added to the residue, extracted three times with chloroform, and washed with saturated saline.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was separated and purified by silica gel column chromatography (elution solvent: 20% ethyl acetate / hexane) and recrystallized from heptane to give the title compound 11, 1.71 g as a white powder.
(82%).

Mp: 69.5 to 70.3 ° C. Elemental analysis _{(C 19 H 28 N 4 O} 2) theory (%) C66.25, H8.19, N16.27 Found (%) C66.00, H8.55, N16.49 IR (KBr) νmax (cm ^-1 ): 1696,1660,1541,1457 NMR (CDCl ₃ ; 270 MHz) δ (ppm); 4.08 (t, 2H), 3.96 (t,
2H), 3.90 (s, 3H), 1.90 to 1.60 (m, 5H), 1.40 to 1.28
(M, 2H), 1.05-0.90 (m, 6H), 0.70-0.60 (m, 2H), 0.5
0 to 0.40 (m, 2H), 0.30 to 0.15 (m, 4H) Example 12. 8- (1,1-dicyclopropylmethyl) -3-propyl-6-thioxanthine (compound 12) 4.00 g (13.9 mmol) of the resulting compound 10 were heated under reflux for 3 hours with 5.03 g (22.6 mmol) of phosphorus pentasulfide in 80 ml of pyridine. After cooling, the reaction mixture was poured into 250 ml of ice water, and the precipitate was removed. The liquid was concentrated to about 1/4, and the precipitate was collected again. The precipitates were combined and suspended in 2N sodium hydroxide (80 ml) to separate insolubles. The solution was neutralized and the precipitated crystals were recrystallized from ethanol-water to give 3.52 g (832) of the title compound as pale yellow needles.
%).

Mp: 219.4~219.8 ℃ IR (KBr) νmax (cm -1): 1661,1606,1570,1505 NMR (DMSO-d 6; 90MHz) δ (ppm): 12.9 (brs, 1H), 12.1
(Brs, 1H), 3.90 (t, 2H), 1.90 to 0.01 (m, 16H) MS (m / e): 304 (M ⁺ ) Example 13. 7-Ethyl-8- (1,1-dicyclo) Propylmethyl)-
1,3-Dipropylxanthine The same operation as in Example 11 was carried out using 2.00 g (6.05 mmol) of the compound 1 obtained in Example 1 and 0.97 ml (12.1 mmol) of ethyl iodide to give a pale yellow powder. This gave 1.53 g (71%) of the title compound 13.

Melting point: 80.4-82.7 ° C IR (KBr) νmax (cm ⁻¹ ): 1700, 1659, 1539, 1417 NMR (CDCl ₃ ; 90 MHz) δ (ppm): 4.22 (q, 2H, J = 7 Hz), 4.
15 ~ 3.80 (m, 4H), 1.40 (t, 3H, J = 7Hz), 2.00 ~ 0.20
(M, 21H) MS (m / e): 358 (M ⁺ ) Example 14.8- (1,1-Dicyclopropylmethyl) -1,3-dipropyl-7-propylxanthine (Compound 14) Example Using 2.00 g (6.05 mmol) of compound 1 obtained in 1 and 1.18 ml (12.1 mmol) of propyl iodide,
The same operation as in Example 11 was performed, and the product was recrystallized from ethanol-water to give 1.85 g (82%) of the title compound 14 as white crystals.

Mp: 93.2~99.6 ℃ IR (KBr) νmax (cm -1): 1702,1660,1541,1416 NMR (CDCl 3; 90MHz) δ (ppm): 4.25~3.75 (m, 6H), 2.0
0 to 0.20 (m, 26H) MS (m / e): 372 (M ⁺ ) Effect of the Invention According to the present invention, a novel xanthine derivative having a diuretic effect, a renal protective effect and a vasodilatory effect is provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/52 ACV A61K 31/52 ACV ACX ACX (72) Inventor Hiromi Nonaka 580-71 Tokukura, Shimizu-cho, Shizuoka-gun, Shizuoka Aki Ki (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 473/02-473/22 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) Expression (Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl, and R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alicyclic alkyl or substituted or unsubstituted Wherein X ¹ and X ² are the same or different and each represent an oxygen or sulfur atom) or a pharmaceutically acceptable salt thereof.